Systems and methods for cross-linking treatments of an eye

ABSTRACT

A system for corneal treatment includes a light source that activates cross-linking in at least one selected region of a cornea treated with a cross-linking agent. The light source delivers photoactivating light to the at least one selected region of the cornea according to a set of parameters. The system includes a controller that receives input relating to the cross-linking agent and the set of parameters. The controller includes computer-readable storage media storing: (A) program instructions for determining cross-linking resulting from reactions involving ROS including at least peroxides, superoxides, and hydroxyl radicals, and (B) program instructions for determining cross-linking from reactions not involving oxygen. The controller executes the program instructions to output a calculated amount of cross-linking in the at least one selected region of the cornea. In response to the calculated amount of cross-linking, the light source adjusts at least one value in the set of parameters.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of PCTApplication No. PCT/US2015/057628, filed on Oct. 27, 2015, which claimspriority to U.S. Provisional Patent Application No. 62/069,094, filedOct. 27, 2014, the contents of these application being incorporatedentirely herein by reference.

BACKGROUND OF THE INVENTION Field of the Invention

The present disclosure pertains to systems and methods for treatingdisorders of the eye, and more particularly, to systems and methods forcross-linking treatments of the eye.

Description of Related Art

Cross-linking treatments may be employed to treat eyes suffering fromdisorders, such as keratoconus. In particular, keratoconus is adegenerative disorder of the eye in which structural changes within thecornea cause it to weaken and change to an abnormal conical shape.Cross-linking treatments can strengthen and stabilize areas weakened bykeratoconus and prevent undesired shape changes.

Cross-linking treatments may also be employed after surgical procedures,such as Laser-Assisted in situ Keratomileusis (LASIK) surgery. Forinstance, a complication known as post-LASIK ectasia may occur due tothe thinning and weakening of the cornea caused by LASIK surgery. Inpost-LASIK ectasia, the cornea experiences progressive steepening(bulging). Accordingly, cross-linking treatments can strengthen andstabilize the structure of the cornea after LASIK surgery and preventpost-LASIK ectasia.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates an example system that delivers a cross-linking agentand photoactivating light to a cornea of an eye in order to generatecross-linking of corneal collagen, according to aspects of the presentdisclosure.

FIGS. 2A-B illustrate a diagram for photochemical kinetic reactionsinvolving riboflavin and photoactivating light (e.g., ultraviolet A(UVA) light) applied during a corneal cross-linking treatment, accordingto aspects of the present disclosure.

FIGS. 3A-C illustrate graphs showing the correlation between modelvalues and experimental data for oxygen depletion experiments, where themodel values are based on a model of photochemical kinetic reactionsaccording to aspects of the present disclosure.

FIG. 4 illustrates a graph showing the correlation between model valuesand experimental data for non-linear optical microscopy fluorescenceexperiments, where the model values are based on a model ofphotochemical kinetic reactions according to aspects of the presentdisclosure.

FIGS. 5A-D illustrate graphs showing the correlation between modelvalues and experimental data for fluorescence data based on papaindigestion method experiments, where the model values are based on amodel of photochemical kinetic reactions according to aspects of thepresent disclosure.

FIGS. 6A-B illustrate graphs showing the correlation between modelvalues and experimental data for corneal stromal demarcation lineexperiments, where the model values are based on a model ofphotochemical kinetic reactions according to aspects of the presentdisclosure.

FIGS. 7A-C illustrate graphs of cross-link profiles for treatments usingdifferent protocols, as generated by a model of photochemical kineticreactions according to aspects of the present disclosure.

FIGS. 8A-C illustrate graphs of cross-link profiles for treatments usingdifferent protocols, as generated by a model of photochemical kineticreactions, where the cross-link profiles are evaluated to determine thedepth for a demarcation line for each protocol according to aspects ofthe present disclosure.

FIGS. 9A-B illustrate graphs of demarcation depth versus dose ofphotoactivating light based on cross-link profiles for treatments usingdifferent protocols, as generated by a model of photochemical kineticreactions according to aspects of the present disclosure.

FIG. 10 illustrates a graph of cross-link profiles for treatments usingdifferent protocols as generated by a model of photochemical kineticreactions, where the cross-link profiles are evaluated to determine thedepth for a demarcation line for each protocol according to aspects ofthe present disclosure.

FIG. 11 illustrates the measurement of maximum keratometry (K_(max)) atsix and twelve months relative to a baseline for corneas that wereexperimentally treated according to the protocols employed for FIG. 10.

FIG. 12A illustrates a graph that plots, for the biomechanical stiffnessdepth determined for each protocol in FIG. 10, the experimental changeof K_(max) for months six and twelve corresponding to the respectiveprotocol, according to aspects of the present disclosure.

FIG. 12B illustrates a graph that plots, for the area above thedemarcation line for each protocol in FIG. 10, the experimental changeof K_(max) for months six and twelve corresponding to the respectiveprotocol, according to aspects of the present disclosure.

FIG. 13 illustrates an example system employing a model of photochemicalkinetic reactions according to aspects of the present disclosure.

FIG. 14 illustrates an example system employing a model of photochemicalkinetic reactions to provide treatment parameters for achieving desiredbiomechanical changes according to aspects of the present disclosure.

FIG. 15 an example method employing a model of photochemical kineticreactions to determine treatment parameters for achieving desiredbiomechanical changes according to aspects of the present disclosure.

SUMMARY

According to aspects of the present disclosure, an example system forcorneal treatment includes a light source configured to activatecross-linking in at least one selected region of a cornea treated with across-linking agent. The light source is configured to deliverphotoactivating light to the at least one selected region of the corneaaccording to a set of parameters. The system also includes a controllerconfigured to receive input relating to the cross-linking agent and theset of parameters for the delivery of the photoactivating light. Thecontroller includes computer-readable storage media storing: (A) a firstset of program instructions for determining, from the input,cross-linking resulting from reactions involving reactive oxygen species(ROS) including at least peroxides, superoxides, and hydroxyl radicals,and (B) a second set of program instructions for determining, from theinput, cross-linking from reactions not involving oxygen. The controlleris configured to execute the first and second sets of programinstructions to output a calculated amount of cross-linking in the atleast one selected region of the cornea. In response to the calculatedamount of cross-linking output by the controller, the light source isconfigured to adjust at least one value in the set of parameters for thedelivery of the photoactivating light.

According to further aspects of the present disclosure, an examplesystem for conical treatment includes a light source configured toactivate cross-linking in at least one selected region of a corneatreated with a cross-linking agent. The light source is configured todeliver photoactivating light to the at least one selected region of thecornea according to a set of parameters. The system also includes anoxygen source and an oxygen delivery device configured to provide aconcentration of oxygen from the oxygen source to the at least oneselected region of the cornea. The system also includes a controllerconfigured to receive input relating to the cross-linking agent, the setof parameters for the delivery of the photoactivating light, and theconcentration of oxygen. The controller includes computer-readablestorage media storing: (A) a first set of program instructions fordetermining, from the input, cross-linking resulting from reactionsinvolving reactive oxygen species (ROS) including at least peroxides,superoxides, and hydroxyl radicals, and (B) a second set of programinstructions for determining, from the input, cross-linking fromreactions not involving oxygen. The controller is configured to executethe first and second sets of program instructions to output a calculatedamount of cross-linking in the at least one selected region of thecornea, the calculated amount of cross-linking indicating athree-dimensional distribution of cross-links. In response to thecalculated amount of the cross-linking activity output by thecontroller, at least one of: (i) the light source is configured toadjust at least one value in the set of parameters for the delivery ofthe photoactivating light, or (ii) the oxygen delivery device isconfigured to adjust a value of the concentration of oxygen delivered tothe at least one selected region of the cornea.

According to yet further aspects of the present disclosure, an examplesystem for corneal treatment includes an illumination system configuredto deliver photoactivating light to a cross-linking agent applied to acornea. The photoactivating light generates cross-linking activity withthe cross-linking agent. The system also includes a controller includingone or more processors and computer-readable storage media. Thecontroller is configured to receive input relating to a desiredbiomechanical change in the cornea and to execute, with the one or moreprocessors, program instructions stored on the storage media todetermine, from a photochemical kinetic model, a three-dimensionaldistribution of cross-links for the cornea to achieve the desiredbiomechanical change in the cornea. The photochemical kinetic modelcalculates the distribution of cross-links based on cross-linking from(A) reactions involving reactive oxygen species (ROS) including at leastperoxides, superoxides, and hydroxyl radicals, and (B) reactions notinvolving oxygen. The controller is configured to execute the programinstructions also to determine at least one set of treatment parametersto achieve the distribution of cross-links. The at least one set oftreatment parameters includes illumination parameters for the deliveryof the photoactivating light by the illumination system. In response tothe determination of the at least one set of treatment parameters, theillumination system is configured to deliver the photoactivating lightto the cornea according to the illumination parameters.

In some embodiments, the controller may be configured to execute theprogram instructions to determine a plurality of sets of treatmentparameters to achieve the distribution of cross-links. The illuminationsystem is configured to deliver the photoactivating light according tothe illumination parameters in a selected one of the sets of treatmentparameters.

In further embodiments, the controller may be configured to receiveinformation relating to one or more preferences for the treatmentparameters and to execute further program instructions to determine theselected set of treatment parameters according to the one or morepreferences.

DESCRIPTION

FIG. 1 illustrates an example treatment system 100 for generatingcross-linking of collagen in a cornea 2 of an eye 1. The treatmentsystem 100 includes an applicator 132 for applying a cross-linking agent130 to the cornea 2. In example embodiments, the applicator 132 may bean eye dropper, syringe, or the like that applies the photosensitizer130 as drops to the cornea 2. The cross-linking agent 130 may beprovided in a formulation that allows the cross-linking agent 130 topass through the corneal epithelium 2 a and to underlying regions in thecorneal stroma 2 b. Alternatively, the corneal epithelium 2 a may beremoved or otherwise incised to allow the cross-linking agent 130 to beapplied more directly to the underlying tissue.

The treatment system 100 includes an illumination system with a lightsource 110 and optical elements 112 for directing light to the cornea 2.The light causes photoactivation of the cross-linking agent 130 togenerate cross-linking activity in the cornea 2. For example, thecross-linking agent may include riboflavin and the photoactivating lightmay be ultraviolet A (UVA) (e.g., 365 nm) light. Alternatively, thephotoactivating light may have another wavelength, such as a visiblewavelength (e.g., 452 nm). As described further below, cornealcross-linking improves corneal strength by creating chemical bondswithin the corneal tissue according to a system of photochemical kineticreactions. For instance, riboflavin and the photoactivating light areapplied to stabilize and/or strengthen corneal tissue to addressdiseases such as keratoconus or post-LASIK ectasia.

The treatment system 100 includes one or more controllers 120 thatcontrol aspects of the system 100, including the light source 110 and/orthe optical elements 112. In an implementation, the cornea 2 can be morebroadly treated with the cross-linking agent 130 (e.g., with an eyedropper, syringe, etc.), and the photoactivating light from the lightsource 110 can be selectively directed to regions of the treated cornea2 according to a particular pattern.

The optical elements 112 may include one or more mirrors or lenses fordirecting and focusing the photoactivating light emitted by the lightsource 110 to a particular pattern on the cornea 2. The optical elements112 may further include filters for partially blocking wavelengths oflight emitted by the light source 110 and for selecting particularwavelengths of light to be directed to the cornea 2 for activating thecross-linking agent 130. In addition, the optical elements 112 mayinclude one or more beam splitters for dividing a beam of light emittedby the light source 110, and may include one or more heat sinks forabsorbing light emitted by the light source 110. The optical elements112 may also accurately and precisely focus the photo-activating lightto particular focal planes within the cornea 2, e.g., at a particulardepths in the underlying region 2 b where cross-linking activity isdesired.

Moreover, specific regimes of the photoactivating light can be modulatedto achieve a desired degree of cross-linking in the selected regions ofthe cornea 2. The one or more controllers 120 may be used to control theoperation of the light source 110 and/or the optical elements 112 toprecisely deliver the photoactivating light according to any combinationof: wavelength, bandwidth, intensity, power, location, depth ofpenetration, and/or duration of treatment (the duration of the exposurecycle, the dark cycle, and the ratio of the exposure cycle to the darkcycle duration).

The parameters for photoactivation of the cross-linking agent 130 can beadjusted, for example, to reduce the amount of time required to achievethe desired cross-linking. In an example implementation, the time can bereduced from minutes to seconds. While some configurations may apply thephotoactivating light at an irradiance of 5 mW/cm², larger irradiance ofthe photoactivating light, e.g., multiples of 5 mW/cm², can be appliedto reduce the time required to achieve the desired cross-linking. Thetotal dose of energy absorbed in the cornea 2 can be described as aneffective dose, which is an amount of energy absorbed through an area ofthe corneal epithelium 2 a. For example the effective dose for a regionof the corneal surface 2A can be, for example, 5 J/cm², or as high as 20J/cm² or 30 J/cm². The effective dose described can be delivered from asingle application of energy, or from repeated applications of energy.

The optical elements 112 of the treatment system 100 may include adigital micro-mirror device (DMD) to modulate the application ofphotoactivating light spatially and temporally. Using DMD technology,the photoactivating light from the light source 110 is projected in aprecise spatial pattern that is created by microscopically small mirrorslaid out in a matrix on a semiconductor chip. Each mirror represents oneor more pixels in the pattern of projected light. With the DMD one canperform topography guided cross-linking. The control of the DMDaccording to topography may employ several different spatial andtemporal irradiance and dose profiles. These spatial and temporal doseprofiles may be created using continuous wave illumination but may alsobe modulated via pulsed illumination by pulsing the illumination sourceunder varying frequency and duty cycle regimes as described above.Alternatively, the DMD can modulate different frequencies and dutycycles on a pixel by pixel basis to give ultimate flexibility usingcontinuous wave illumination. Or alternatively, both pulsed illuminationand modulated DMD frequency and duty cycle combinations may be combined.This allows for specific amounts of spatially determined cornealcross-linking. This spatially determined cross-linking may be combinedwith dosimetry, interferometry, optical coherence tomography (OCT),corneal topography, etc., for pre-treatment planning and/or real-timemonitoring and modulation of corneal cross-linking during treatment.Additionally, pre-clinical patient information may be combined withfinite element biomechanical computer modeling to create patientspecific pre-treatment plans.

To control aspects of the delivery of the photoactivating light,embodiments may also employ aspects of multiphoton excitationmicroscopy. In particular, rather than delivering a single photon of aparticular wavelength to the cornea 2, the treatment system 100 maydeliver multiple photons of longer wavelengths, i.e., lower energy, thatcombine to initiate the cross-linking. Advantageously, longerwavelengths are scattered within the cornea 2 to a lesser degree thanshorter wavelengths, which allows longer wavelengths of light topenetrate the cornea 2 more efficiently than shorter wavelength light.Shielding effects of incident irradiation at deeper depths within thecornea are also reduced over conventional short wavelength illuminationsince the absorption of the light by the photosensitizer is much less atthe longer wavelengths. This allows for enhanced control over depthspecific cross-linking. For example, in some embodiments, two photonsmay be employed, where each photon carries approximately half the energynecessary to excite the molecules in the cross-linking agent 130 togenerate the photochemical kinetic reactions described further below.When a cross-linking agent molecule simultaneously absorbs both photons,it absorbs enough energy to release reactive radicals in the cornealtissue. Embodiments may also utilize lower energy photons such that across-linking agent molecule must simultaneously absorb, for example,three, four, or five, photons to release a reactive radical. Theprobability of the near-simultaneous absorption of multiple photons islow, so a high flux of excitation photons may be required, and the highflux may be delivered through a femtosecond laser.

A large number of conditions and parameters affect the cross-linking ofcorneal collagen with the cross-linking agent 130. For example, when thecross-linking agent 130 is riboflavin and the photoactivating light isUVA light, the irradiance and the dose both affect the amount and therate of cross-linking. The UVA light may be applied continuously(continuous wave (CW)) or as pulsed light, and this selection has aneffect on the amount, the rate, and the extent of cross-linking.

If the UVA light is applied as pulsed light, the duration of theexposure cycle, the dark cycle, and the ratio of the exposure cycle tothe dark cycle duration have an effect on the resulting cornealstiffening. Pulsed light illumination can be used to create greater orlesser stiffening of corneal tissue than may be achieved with continuouswave illumination for the same amount or dose of energy delivered. Lightpulses of suitable length and frequency may be used to achieve moreoptimal chemical amplification. For pulsed light treatment, the on/offduty cycle may be between approximately 1000/1 to approximately 1/1000;the irradiance may be between approximately 1 mW/cm² to approximately1000 mW/cm² average irradiance, and the pulse rate may be betweenapproximately 0.01 HZ to approximately 1000 Hz or between approximately1000 Hz to approximately 100,000 Hz.

The treatment system 100 may generate pulsed light by employing a DMD,electronically turning the light source 110 on and off, and/or using amechanical or opto-electronic (e.g., Pockels cells) shutter ormechanical chopper or rotating aperture. Because of the pixel specificmodulation capabilities of the DMD and the subsequent stiffnessimpartment based on the modulated frequency, duty cycle, irradiance anddose delivered to the cornea, complex biomechanical stiffness patternsmay be imparted to the cornea to allow for various amounts of refractivecorrection. These refractive corrections, for example, may involvecombinations of myopia, hyperopia, astigmatism, irregular astigmatism,presbyopia and complex corneal refractive surface corrections because ofophthalmic conditions such as keratoconus, pellucid marginal disease,post-lasik ectasia, and other conditions of corneal biomechanicalalteration/degeneration, etc. A specific advantage of the DMD system andmethod is that it allows for randomized asynchronous pulsed topographicpatterning, creating a non-periodic and uniformly appearing illuminationwhich eliminates the possibility for triggering photosensitive epilepticseizures or flicker vertigo for pulsed frequencies between 2 Hz and 84Hz.

Although example embodiments may employ stepwise on/off pulsed lightfunctions, it is understood that other functions for applying light tothe cornea may be employed to achieve similar effects. For example,light may be applied to the cornea according to a sinusoidal function,sawtooth function, or other complex functions or curves, or anycombination of functions or curves. Indeed, it is understood that thefunction may be substantially stepwise where there may be more gradualtransitions between on/off values. In addition, it is understood thatirradiance does not have to decrease down to a value of zero during theoff cycle, and may be above zero during the off cycle. Desired effectsmay be achieved by applying light to the cornea according to a curvevarying irradiance between two or more values.

Examples of systems and methods for delivering photoactivating light aredescribed, for example, in U.S. Patent Application Publication No.2011/0237999, filed Mar. 18, 2011 and titled “Systems and Methods forApplying and Monitoring Eye Therapy,” U.S. Patent ApplicationPublication No. 2012/0215155, filed Apr. 3, 2012 and titled “Systems andMethods for Applying and Monitoring Eye Therapy,” and U.S. PatentApplication Publication No. 2013/0245536, filed Mar. 15, 2013 and titled“Systems and Methods for Corneal Cross-Linking with Pulsed Light,” thecontents of these applications being incorporated entirely herein byreference.

The addition of oxygen also affects the amount of corneal stiffening. Inhuman tissue, O₂ content is very low compared to the atmosphere. Therate of cross-linking in the cornea, however, is related to theconcentration of O₂ when it is irradiated with photoactivating light.Therefore, it may be advantageous to increase or decrease theconcentration of O₂ actively during irradiation to control the rate ofcross-linking until a desired amount of cross-linking is achieved.Oxygen may be applied during the cross-linking treatments in a number ofdifferent ways. One approach involves supersaturating the riboflavinwith O₂. Thus, when the riboflavin is applied to the eye, a higherconcentration of O₂ is delivered directly into the cornea with theriboflavin and affects the reactions involving O₂ when the riboflavin isexposed to the photoactivating light. According to another approach, asteady state of O₂ (at a selected concentration) may be maintained atthe surface of the cornea to expose the cornea to a selected amount ofO₂ and cause O₂ to enter the cornea. As shown in FIG. 1, for instance,the treatment system 100 also includes an oxygen source 140 and anoxygen delivery device 142 that optionally delivers oxygen at a selectedconcentration to the cornea 2. Example systems and methods for applyingoxygen during cross-linking treatments are described, for example, inU.S. Pat. No. 8,574,277, filed Oct. 21, 2010 and titled “Eye Therapy,”U.S. Patent Application Publication No. 2013/0060187, filed Oct. 31,2012 and titled “Systems and Methods for Corneal Cross-Linking withPulsed Light,” the contents of these applications being incorporatedentirely herein by reference.

When riboflavin absorbs radiant energy, especially light, it undergoesphoto activation. There are two photochemical kinetic pathways forriboflavin photoactivation, Type I and Type II. Some of the reactionsinvolved in both the Type I and Type II mechanisms are as follows:

Common Reactions:

Rf→Rf ₁ *,I;  (r1)

Rf ₁ *→Rf,κ1;  (r2)

Rf ₁ *→Rf ₃*,κ2;  (r3)

Type I Reactions:

Rf ₃ *+DH→RfH ⁻ +D ⁻,κ3;  (r4)

2RfH ⁻ →Rf+RfH ₂,κ4;  (r5)

Type II Reactions:

Rf ₃ *+O ₂ →Rf+O ₂ ¹,κ5;  (r6)

DH+O ₂ ¹ →D _(ox),κ6;  (r7)

D _(ox) +DH→D−D,κ7;CXL  (r8)

In the reactions described herein, Rf represents riboflavin in theground state. Rf*₁ represents riboflavin in the excited singlet state.Rf*₃ represents riboflavin in a triplet excited state. Rf*⁻ is thereduced radical anion form of riboflavin. RfH* is the radical form ofriboflavin. RfH₂ is the reduced form of riboflavin. DH is the substrate.DH*⁺ is the intermediate radical cation. D* is the radical. D_(ox) isthe oxidized form of the substrate.

Riboflavin is excited into its triplet excited state Rf*₃ as shown inreactions (r1) to (r3). From the triplet excited state Rf*₃, theriboflavin reacts further, generally according to Type I or Type IImechanisms. In the Type I mechanism, the substrate reacts with theexcited state riboflavin to generate radicals or radical ions,respectively, by hydrogen atoms or electron transfer. In Type IImechanism, the excited state riboflavin reacts with oxygen to formsinglet molecular oxygen. The singlet molecular oxygen then acts ontissue to produce additional cross-linked bonds.

Oxygen concentration in the cornea is modulated by UVA irradiance andtemperature and quickly decreases at the beginning of UVA exposure.Utilizing pulsed light of a specific duty cycle, frequency, andirradiance, input from both Type I and Type II photochemical kineticmechanisms can be employed to achieve a greater amount of photochemicalefficiency. Moreover, utilizing pulsed light allows regulating the rateof reactions involving riboflavin. The rate of reactions may either beincreased or decreased, as needed, by regulating, one of the parameterssuch as the irradiance, the dose, the on/off duty cycle, riboflavinconcentration, soak time, and others. Moreover, additional ingredientsthat affect the reaction and cross-linking rates may be added to thecornea.

If UVA radiation is stopped shortly after oxygen depletion, oxygenconcentrations start to increase (replenish). Excess oxygen may bedetrimental in the corneal cross-linking process because oxygen is ableto inhibit free radical photopolymerization reactions by interactingwith radical species to form chain-terminating peroxide molecules. Thepulse rate, irradiance, dose, and other parameters can be adjusted toachieve a more optimal oxygen regeneration rate. Calculating andadjusting the oxygen regeneration rate is another example of adjustingthe reaction parameters to achieve a desired amount of cornealstiffening.

Oxygen content may be depleted throughout the cornea, by variouschemical reactions, except for the very thin corneal layer where oxygendiffusion is able to keep up with the kinetics of the reactions. Thisdiffusion-controlled zone will gradually move deeper into the cornea asthe reaction ability of the substrate to uptake oxygen decreases.

Riboflavin is reduced (deactivated) reversibly or irreversibly and/orphoto-degraded to a greater extent as irradiance increases. Photonoptimization can be achieved by allowing reduced riboflavin to return toground state riboflavin in Type I reactions. The rate of return ofreduced riboflavin to ground state in Type I reactions is determined bya number of factors. These factors include, but are not limited to,on/off duty cycle of pulsed light treatment, pulse rate frequency,irradiance, and dose. Moreover, the riboflavin concentration, soak time,and addition of other agents, including oxidizers, affect the rate ofoxygen uptake. These and other parameters, including duty cycle, pulserate frequency, irradiance, and dose can be selected to achieve moreoptimal photon efficiency and make efficient use of both Type I as wellas Type II photochemical kinetic mechanisms for riboflavinphotosensitization. Moreover, these parameters can be selected in such away as to achieve a more optimal chemical amplification effect.

In addition to the photochemical kinetic reactions (r1)-(r8) above,however, the present inventors have identified the followingphotochemical kinetic reactions (r9)-(r26) that also occur duringriboflavin photoactivation:

$\begin{matrix}{\left. {{Rf}_{3}}^{*}\rightarrow{Rf} \right.,{{\kappa 8};}} & ({r9}) \\{\left. {{{Rf}_{3}}^{*} + {Rf}}\rightarrow{2{{Rf}H}^{\cdot}} \right.,{{\kappa 9};}} & ({r10}) \\{\left. {{{Rf}H}_{2} + O_{2}}\rightarrow{{{Rf}H}^{\cdot} + H^{+} + {O_{2}}^{-}} \right.,{{\kappa 10};}} & ({r11}) \\{\left. {{{Rf}H}^{\cdot} + O_{2}}\rightarrow{{Rf} + H^{+} + {O_{2}}^{-}} \right.,{{\kappa 11};}} & ({r12}) \\{\left. {{2{{Rf}H}_{2}} + {O_{2}}^{-}}\rightarrow{{2{{Rf}H}^{\cdot}} + {H_{2}O_{2}}} \right.,{{\kappa 12};}} & ({r13}) \\{\left. {{2{{Rf}H}^{\cdot}} + {O_{2}}^{-}}\rightarrow{{2{Rf}} + {H_{2}O_{2}}} \right.,{{\kappa 13};}} & ({r14}) \\{\left. {{{Rf}H}^{\cdot} + {H_{2}O_{2}}}\rightarrow{{OH}^{\cdot} + {Rf} + {H_{2}O}} \right.,{{\kappa 14};}} & ({r15}) \\{\left. {{OH}^{\cdot} + {DH}}\rightarrow{D^{\cdot} + {H_{2}O}} \right.,{{\kappa 15};}} & ({r16}) \\{\left. {D^{\cdot} + D^{\cdot}}\rightarrow{D - D} \right.,{{\kappa 16};\mspace{14mu}{C\; X\; L}}} & ({r17}) \\{\left. O_{2}^{1}\rightarrow O_{2} \right.,{{\kappa 18};}} & ({r18}) \\{\left. {D^{\cdot} + {{Rf}H}_{2}}\rightarrow{{{Rf}H}^{\cdot} + {DH}} \right.,{{\kappa 19};}} & ({r19}) \\{{{Rf} + {{Rf}_{\underset{\kappa_{a}^{-}}{\leftarrow}}^{\overset{\kappa_{a}^{+}}{\rightarrow}}A_{1}}},{\kappa_{a} = {\kappa_{a}^{+}/\kappa_{a}^{-}}}} & ({r20}) \\{{{{Rf}H}_{2} + {{{{Rf}H}_{2}}_{\underset{\kappa_{a}^{-}}{\leftarrow}}^{\overset{\kappa_{a}^{+}}{\rightarrow}}A_{2}}},{\kappa_{a} = {\kappa_{a}^{+}/\kappa_{a}^{-}}}} & ({r21}) \\{{{Rf} + {{{{Rf}H}_{2}}_{\underset{\kappa_{b}^{-}}{\leftarrow}}^{\overset{\kappa_{b}^{+}}{\rightarrow}}A_{3}}},{\kappa_{b} = {\kappa_{b}^{+}/\kappa_{b}^{-}}}} & ({r22}) \\{\left. {{{Rf}_{1}}^{*} + A}\rightarrow{{Rf} + A} \right.,\kappa_{1a}} & ({r23}) \\{\left. {{{Rf}_{3}}^{*} + A}\rightarrow{{Rf} + A} \right.,\kappa_{3a}} & ({r24}) \\{\left. {2O_{2}^{-}}\rightarrow{O_{2} + {H_{2}O_{2}}} \right.,\kappa_{12}} & ({r25}) \\{\left. {{OH}^{{^\circ}} + {C\; X\; L}}\rightarrow{{inert}\mspace{14mu}{products}} \right.,\kappa_{OH}} & ({r26})\end{matrix}$

FIG. 2A illustrates a diagram for the photochemical kinetic reactionsprovided in reactions (r1) through (r26) above. The diagram summarizesphotochemical transformations of riboflavin (Rf) under UVAphotoactivating light and its interactions with various donors (DH) viaelectron transfer. As shown, cross-linking activity occurs: (A) throughthe presence of singlet oxygen in reactions (r6) through (r8) (Type IImechanism); (B) without using oxygen in reactions (r4) and (r17) (Type Imechanism); and (C) through the presence of peroxide (H₂O₂), superoxide(O₂ ⁻), and hydroxyl radicals (.OH) in reactions (r13) through (r17).

As shown in FIG. 2A, the present inventors have also determined that thecross-linking activity is generated to a greater degree from reactionsinvolving peroxide, superoxide, and hydroxyl radicals. Cross-linkingactivity is generated to a lesser degree from reactions involvingsinglet oxygen and from non-oxygen reactions. Some models based on thereactions (r1)-(r26) may account for the level of cross-linking activitygenerated by the respective reactions. For instance, where singletoxygen plays a smaller role in generating cross-linking activity, modelsmay be simplified by treating the cross-linking activity resulting fromsinglet oxygen as a constant.

All the reactions start from Rf₃* as provided in reactions (r1)-(r3).The quenching of Rf₃* occurs through chemical reaction with ground stateRf in reaction (r10), and through deactivation by the interaction withwater in reaction (r9).

As described above, excess oxygen may be detrimental in cornealcross-linking process. As shown in FIG. 2A, when the system becomesphoton-limited and oxygen-abundant, cross-links can be broken fromfurther reactions involving superoxide, peroxide, and hydroxyl radicals.Indeed, in some cases, excess oxygen may result in net destruction ofcross-links versus generation of cross-links.

As described above, a large variety of factors affect the rate of thecross-linking reaction and the amount of biomechanical stiffnessachieved due to cross-linking. A number of these factors areinterrelated, such that changing one factor may have an unexpectedeffect on another factor. However, a more comprehensive model forunderstanding the relationship between different factors forcross-linking treatment is provided by the photochemical kineticreactions (r1)-(r26) identified above. Accordingly, systems and methodscan adjust various parameters for cross-linking treatment according tothis photochemical kinetic cross-linking model, which provides a unifieddescription of oxygen dynamics and cross-linking activity. The model canbe employed to evaluate expected outcomes based on differentcombinations of treatment parameters and to identify the combination oftreatment parameters that provides the desired result. The parameters,for example, may include, but is not limited to: the concentration(s)and/or soak times of the applied cross-linking agent; the dose(s),wavelength(s), irradiance(s), duration(s), and/or on/off duty cycle(s)of the photoactivating light; the oxygenation conditions in the tissue;and/or presence of additional agents and solutions.

A model based on the reactions (r1)-(r19) has been validated by at leastfour different methods of evaluating cross-linking activity:

-   -   Oxygen depletion experiments    -   Non-linear optical microscopy fluorescence experiments    -   Fluorescence data based on papain digestion method experiments    -   Corneal stromal demarcation line correlation experiments

For the oxygen depletion experiments, O₂ concentrations were measuredand calculated at a depth of approximately 100 μm to approximately 200μm for corneas treated with riboflavin. FIG. 3A illustrates a graph ofdata showing the correlation between the theoretical values based on themodel and experimental data for corneas exposed to continuous wave UVAphotoactivating light at an irradiance of 3 mW/cm². FIGS. 3B-Cillustrate graphs of data showing the correlation between model valuesand experimental data for corneas exposed to long term pulses and shortterm pulses, respectively, at an irradiance of 3 mW/cm².

For the non-linear optical microscopy fluorescence experiments, thecross-linking profiles based on corneal depth were determined forcorneas treated with riboflavin and exposed to UVA photoactivating lightat an irradiance of 3 mW/cm². FIG. 4 illustrates a graph of data showingthe correlation between model and experimental data for corneas exposedfor 15 minutes and 30 minutes. The third party experimental data waspublished in Dongyul Chai et al. “Quantitative Assessment ofUVA-riboflavin Corneal Cross-Linking Using Nonlinear OpticalMicroscopy.” Investigative Ophthalmology & Visual Science. June 2011,Vol. 52, No. 7, pp. 4231-4238, the contents of which are incorporatedentirely herein by reference.

For the fluorescence data based on papain digestion method experiments,cross-linking concentrations were evaluated based on fluorescent lightintensity. FIG. 5A illustrates a graph of data showing the correlationof model values and experimental data for corneal flaps (taken from 0 toapproximately 100 μm deep) exposed to combinations of riboflavinconcentrations (0.1%, 0.25%, and 0.5%) and 5.4 J/cm² doses of UVAphotoactivating light at irradiances of 3 mW/cm² and 30 mW/cm² for 3minutes and 30 minutes. Similarly, FIG. 5B illustrates a graph of datashowing the correlation of model values and experimental data forcorneal flaps (taken from approximately 100 μm to approximately 200 μmdeep) exposed to combinations of riboflavin concentrations (0.1%, 0.25%,and 0.5%) and 5.4 J/cm² doses of UVA photoactivating light atirradiances of 3 mW/cm² and 30 mW/cm² for 3 minutes and 30 minutes. FIG.5C illustrates a graph of data showing the correlation of model valuesand experimental data for corneal flaps treated with a concentration ofriboflavin and exposed to full oxygen concentration and 5.4 J/cm² and7.2 J/cm² doses of continuous wave UVA photoactivating light atirradiances of 3 mW/cm², 10 mW/cm², 15 mW/cm², 30 mW/cm², 45 mW/cm², 60mW/cm², and 100 mW/cm². FIG. 5D illustrates a graph of data showing thecorrelation of model values and experimental data for corneal flaps(taken from approximately 0 μm to approximately 200 μm deep) treatedwith a concentration of 0.1% riboflavin and exposed to air or fulloxygen concentration and a 5.4 J/cm² doses of continuous wave UVAphotoactivating light at irradiances of 3 mW/cm², 10 mW/cm², 15 mW/cm²,30 mW/cm², 45 mW/cm², 60 mW/cm², and 100 mW/cm².

For the corneal stromal demarcation correlation experiments, cornealstromal demarcation lines were evaluated for treated corneas. Cornealstromal demarcation lines indicate the transition zone betweencross-linked anterior corneal stroma and untreated posterior cornealstroma. Aspects of the method for these experiments are describedfurther by Theo Seiler and Farhad Hafezi. “Corneal Cross-Linking-InducedStromal Demarcation Line.” Cornea, October 2006; 25:1057-59, thecontents of which are incorporated entirely herein by reference. Thecorneal FIG. 6A illustrates a graph of data showing the correlation ofmodel values and experimental data for the depths of corneal stromaldemarcation lines for the protocols described in FIG. 6B.

The four evaluations described above show a strong correlation betweenthe experimental data and the calculations generated by a model based onthe photochemical kinetic reactions identified above. The model isextremely effective and accurate in predicting the results of riboflavincross-linking treatments applied according to various combinations ofparameters. Accordingly, using such a model, systems and methods canmore efficiently and predictably achieve a desired profile ofcross-linking activity throughout the cornea. The model allows thesystems and methods to identify a more optimal combination of parametersfor cross-linking treatment. Therefore, the model can be used todetermine the set up for different aspects of cross-linking treatmentsystems as described above.

As shown in FIG. 2B, aspects of the system of reactions can be affectedby different parameters. For instance, the irradiance at whichphotoactivating light is delivered to the system affects the photonsavailable in the system to generate Rf₃* for subsequent reactions.Additionally, delivering greater oxygen into the system drives theoxygen-based reactions. Meanwhile, pulsing the photoactivating lightaffects the ability of the reduced riboflavin to return to ground stateriboflavin by allowing additional time for oxygen diffusion. Of course,other parameters can be varied to control the system of reactions.

A model based on the photochemical kinetic reactions (r1)-(r26) cangenerate cross-link profiles for treatments using different protocols asshown in FIGS. 7A-C. In particular, each protocol determines the dose ofthe photoactivating UVA light, the irradiance for the UVAphotoactivating light, the treatment time, and the concentration ofoxygen delivered to the corneal surface. The cornea has been treatedwith a formulation including 0.1% concentration riboflavin. FIG. 7Aillustrates cross-link profiles for treatments that deliver a dose of7.2 J/cm² of UVA light under normal (ambient) oxygen according todifferent irradiances and different treatment times. FIG. 7B illustratescross-link profiles for treatments that employ different irradiances ofcontinuous or modulated (pulsed) UVA light and different treatment timesunder normal or 100% oxygen concentration. FIG. 7C illustratescross-link profiles for treatments that deliver an irradiance of 3 mW ofUVA light for 30 minutes with different oxygen conditions (normal, 100%,or 0.01×) at the corneal surface.

The cross-link profiles in FIGS. 7A-C provide the cross-linkconcentration as a function of corneal depth. In general, thethree-dimensional distribution of cross-links in the cornea as indicatedby each cross-link profile depends on the combination of differenttreatment parameters. Protocols employing different sets of treatmentparameters can be provided as input into the model and the model canoutput the resulting three-dimensional distribution of cross-links inthe cornea. Accordingly, the model can be used to select treatmentparameters to achieve the desired distribution of cross-links in thecornea.

As described above, corneal stromal demarcation lines indicate thetransition zone between cross-linked anterior corneal stroma anduntreated posterior corneal stroma. As also shown in FIG. 8A-C,cross-link profiles generated by the model can be evaluated to determinethe depth at which the demarcation line may appear at a cross-linkconcentration of approximately 5 mol/m³. Here, the demarcation line maybe understood as the threshold at which a healing response occurs inresponse to the distribution of cross-links as well as the effect ofreactive oxygen species on the corneal tissue. The cornea has beentreated with a formulation including 0.1% concentration riboflavin. FIG.8A illustrates a cross-link profile for a treatment that delivers a doseof 5.4 J/cm² of photoactivating UVA light under normal oxygen accordingto an irradiance of 3 mW/cm² and a treatment time of 30 minutes. FIG. 8Ashows that a cross-link concentration of approximately 5 mol/m³(demarcation line) occurs at a depth of approximately 290 μm in theresulting cross-link profile. FIG. 8B illustrates cross-link profilesfor treatments that deliver different doses of photoactivating UVA lightaccording to different irradiances and different treatment times undernormal oxygen. FIG. 8C illustrates cross-link profiles for treatmentsthat deliver different doses of photoactivating UVA light according todifferent irradiances and different treatment times under normal or 100%oxygen concentration.

FIGS. 8B-C shows that the depths for the demarcation line vary with thedifferent cross-link profiles generated by the different sets oftreatment parameters. The depths of the demarcation line indicated bythe different cross-link profiles may be employed to select treatmentparameters. For instance, treatment parameters may be selected to ensurethat the cross-links do not occur at a depth where undesired damage mayresult to the endothelium. This analysis allows the treatment system toaccommodate different corneal thicknesses, particularly thin corneas.

Correspondingly, FIGS. 9A-B illustrate graphs of demarcation depth(cross-link concentration of approximately 5 mol/m³) as a function ofdose of UVA photoactivating light. The determination of the demarcationdepths are based on cross-link profiles generated by the model fortreatments using different protocols. The cornea has been treated with aformulation including 0.1% concentration riboflavin. FIG. 9A illustratesgraphs for treatments that deliver continuous or pulsed UVAphotoactivating light according to different irradiances under normaloxygen. FIG. 9B illustrates graphs for treatments that delivercontinuous or pulsed UVA photoactivating light according to differentirradiances under a greater concentration of oxygen.

FIG. 10 illustrates the cross-link profiles for treatments employingdifferent protocols as generated by the model. FIG. 10 also shows ademarcation line that corresponds to biomechanical stiffness thresholdat a cross-link concentration of 10 mol/m³. The demarcation lineintersects the cross-link profiles at varying depths (biomechanicalstiffness depth) based on the different treatment parameters of theprotocols. FIG. 11 illustrates the measurement of maximum keratometry(K_(max)) (diopters) at three, six, and twelve months relative to abaseline for corneas that were experimentally treated according to theprotocols employed for FIG. 10.

FIGS. 12A-B illustrate the correlation between the experimental data ofFIG. 11 and the cross-link profiles generated for FIG. 10 by the model.For the biomechanical stiffness depth determined for each protocol inFIG. 10, FIG. 12A plots the experimental change of K_(max) for monthssix and twelve corresponding to the respective protocol. FIG. 12A alsoshows a quadratic fit of the plotted data for each month six and twelve.The quadratic fit is consistent with the quadratic nature of shearforces (in the x-y plane) resulting from a force placed on a disk (alongthe z-axis) according to thin shell theory.

Meanwhile, for the area above the demarcation line for the cross-linkprofile for each protocol in FIG. 10, FIG. 12B plots the experimentalchange of K_(max) for months six and twelve corresponding to therespective protocol. FIG. 12B also shows a linear fit of the plotteddata for each month six and twelve.

The quadratic fit for the two curves in FIG. 12A are substantiallysimilar. Similarly, the linear fit for the two curves in FIG. 12B aresubstantially similar. The correlations shown in FIGS. 12A-B indicatethat there is a predictable biomechanical/healing response over time fora given set of treatment parameters. In view of the verification of theexperimental data points, the model, as well as thin shell analysis, onecan predictably determine refractive change according to the radius anddepth of the disk corresponding to the myopic correction. In general,the distribution of cross-links effects refractive change. By accuratelydetermining the distribution of cross-links, the model can be employedto determine this refractive change.

According to an embodiment, FIG. 13 illustrates the example system 100employing a model based on the photochemical kinetic reactions(r1)-(r26) identified above to determine an amount of cross-linking thatresults from treatment parameters and/or other related information. Thecontroller 120 includes a processor 122 and computer-readable storagemedia 124. The storage media 124 stores program instructions fordetermining an amount of cross-linking when the photoactivating lightfrom the light source 110 is delivered to a selected region of a corneatreated with a cross-linking agent. In particular, a photochemicalkinetic model 126 based on the reactions (r1)-(r26) may include a firstset of program instructions A for determining cross-linking resultingfrom reactions involving reactive oxygen species (ROS) includingcombinations of peroxides, superoxides, hydroxyl radicals, and/orsinglet oxygen and a second set of program instructions B fordetermining cross-linking from reactions not involving oxygen. Thecontroller 120 receives input relating to treatment parameters and/orother related information. The controller 120 can then execute theprogram instructions A and B to output information relating tothree-dimensional cross-link distribution(s) for the selected region ofthe cornea based on the input. The three-dimensional cross-linkdistribution(s) may then be employed to determine how to control aspectsof the light source 110, the optical elements 112, the cross-linkingagent 130, the applicator 132, the oxygen source 140, and/or oxygendelivery device 142 in order to achieve a desired treatment in selectedregion of the cornea. (Of course, the system 100 shown in FIG. 13 andthis process can be used for treatment of more than one selected regionof the same cornea.)

According to one implementation, the three-dimensional cross-linkdistribution(s) may be evaluated to calculate a threshold depthcorresponding to a healing response due to the cross-links and an effectof the reactive-oxygen species in the selected region of the cornea.Additionally or alternatively, the three-dimensional cross-linkdistribution(s) may be evaluated to calculate a biomechanical tissuestiffness threshold depth corresponding to a biomechanical tissueresponse in the selected region of the cornea. The information on thedepth of the healing response and/or the biomechanical tissue stiffnessin the cornea can be employed to determine how to control aspects of thelight source 110, the optical elements 112, the cross-linking agent 130,the applicator 132, the oxygen source 140, and/or oxygen delivery device142. Certain healing response and/or biomechanical tissue stiffness maybe desired or not desired at certain depths of the cornea.

According to another embodiment, FIG. 14 illustrates the example system100 employing the photochemical kinetic model 126 to determine treatmentparameters for achieving desired biomechanical changes in the cornea,e.g., a refractive correction. As in FIG. 13, the controller 120includes the processor 122 and the computer-readable storage media 124.In the example of FIG. 14, however, the storage media 124 stores programinstructions 125 for determining what treatment parameters may beemployed to achieve desired biomechanical changes. The programinstructions 125 are based on the photochemical kinetic model 126 whichemploy the reactions (r1)-(r26) to determine cross-linking resultingfrom (i) reactions involving reactive oxygen species (ROS) includingcombinations of peroxides, superoxides, hydroxyl radicals, and/orsinglet oxygen and (ii) reactions not involving oxygen.

Using the photochemical kinetic model 126, a three-dimensionaldistribution of resulting cross-links throughout the treated cornealtissue can be determined for a combination of treatment parameters. Asdescribed above, parameters for cross-linking treatment may include: theconcentration(s) and/or soak times of the applied cross-linking agent;the dose(s), wavelength(s), irradiance(s), duration(s), on/off dutycycle(s), and/or other illumination parameters for the photoactivatinglight; the oxygenation conditions in the tissue; and/or presence ofadditional agents and solutions. The resulting distribution ofcross-links determined from the photochemical kinetic model 126 can becorrelated to a particular biomechanical change in the cornea. FIGS.12A-B show, for instance, the correlation between the distribution ofcross-links and refractive change.

As shown in FIG. 14, the controller 120 receives an input 12 relating tothe initial biomechanical state of the cornea and an input 14 indicatinga desired biomechanical change for the cornea, e.g., for refractivecorrection. The initial biomechanical state, for instance, can bedetermined according to approaches described in U.S. Patent ApplicationPublication No. 2012/0215155 referenced above. In some cases, the input12 may be provided by a measurement system communicatively coupled tothe controller 120. It is understood that the initial biomechanicalstate may reflect the state of the cornea prior to any treatment orduring a treatment.

The inputs 12, 14 may be expressed in terms of corneal topography (i.e.,shape), corneal strength (i.e., stiffness), and/or corneal thickness.For instance, the desired biomechanical change for refractive correctionmay be determined from a correction specified (by a practitioner) indiopters, e.g., “a 1.5 diopter correction.”

A desired biomechanical change in the cornea can be correlated to aparticular distribution of cross-links as determined by thephotochemical kinetic model 126. As such, the controller 120 can executethe program instructions 125 to determine the particular distribution ofcross-links 16 that can generate the desired biomechanical changespecified by the input 14 in a cornea having the initial biomechanicalstate specified by the input 12. After determining the distribution ofcross-links 16 for the desired biomechanical change, the controller 120can prescribe a set of treatment parameters for achieving the specifieddistribution of cross-links.

As the studies above establish, however, the distribution of cross-links16 might be achieved in many cases by more than one set of treatmentparameters. For instance, depending on the photochemical kineticreactions, similar distributions of cross-links may be achieved byapplying: (i) a lower dose of photoactivating light for a longer amountof time, or (ii) a higher dose of photoactivating light for a shorteramount of time. Therefore, more than one set of treatment parameters 18for achieving the distribution of cross-links 16 may be identified.

With more than one possible set of treatment parameters 18, apractitioner can optimize the treatment for certain preferredparameters, such as treatment time or dose of photoactivating light. Forinstance, the practitioner may optimize the treatment parameters toachieve shorter treatment times. For this preference, the controller 120may prescribe a set of illumination parameters that provide a largerdose of photoactivating light that yields the distribution ofcross-links 16 over shorter illumination durations. Conversely, thepractitioner may optimize the treatment parameters to employ smallerdoses of photoactivating light. For this second preference, thecontroller 120 may prescribe a set of illumination parameters thatprovide a smaller dose of photoactivating light that yields thedistribution of cross-links 16 over longer illumination durations.

In general, to achieve the distribution of cross-links 16, thecontroller 120 may identify any of the different combinations 18 ofvalues for a set of treatment parameters A, B, C, D, E, etc., asdescribed above. The practitioner can set preferences for one or more ofthese treatment parameters. For instance, the practitioner may initiallyset a preferred value or range of preferred values for parameter A. Inresponse, the controller 120 can specify combinations of values for theremaining parameters B, C, D, E, etc., that meet the preference forparameter A while achieving the distribution of cross-links 16. Thepractitioner may make selections for the values of the parameters B, C,D, and/or E, etc., based on further preferences to arrive at anoptimized set of treatment parameters 18 a. The process of optimizingthe treatment parameters may be iterative as the values for thetreatment parameters are incrementally tuned to meet preferences havingvarying priorities.

In some embodiments, the practitioner may manage the optimizationprocess through a series of selections and other inputs via a userinterface (not shown) coupled to the controller 120. In some cases, theinputs 12, 14 may also be provided through such a user interface.

The final set of treatment parameters 18 a can then be employed todetermine how to control aspects of the light source 110, the opticalelements 112, the cross-linking agent 130, the applicator 132, theoxygen source 140, oxygen delivery device 142, etc., in order to achievea desired treatment in selected region of the cornea.

Correspondingly, FIG. 15 illustrates an example method 200 for employinga model of photochemical kinetic reactions (r1)-(r26) to determinetreatment parameters for achieving desired biomechanical changes. Instep 202, information relating to the initial biomechanical state of acornea is received. In step 204, information relating to a desiredbiomechanical change for the cornea, e.g., for refractive correction, isreceived. In step 206, a distribution of cross-links is determined toachieve the desired biomechanical change in a cornea having the initialbiomechanical state. In step 208, one or more sets of treatmentparameters are determined to achieve the distribution of cross-links. Inassociation with step 208, one or more preferences for treatmentparameters may be received in step 210, and the treatment parameters maybe optimized in step 212 based on the one or more preferences todetermine a final set of treatment parameters that can be implemented ina treatment system (e.g., the example system 100) to achieve thedistribution of cross-links.

As described above, according to some aspects of the present disclosure,some or all of the steps of the above-described and illustratedprocedures can be automated or guided under the control of a controller(e.g., the controller 120). Generally, the controllers may beimplemented as a combination of hardware and software elements. Thehardware aspects may include combinations of operatively coupledhardware components including microprocessors, logical circuitry,communication/networking ports, digital filters, memory, or logicalcircuitry. The controller may be adapted to perform operations specifiedby a computer-executable code, which may be stored on a computerreadable medium.

As described above, the controller may be a programmable processingdevice, such as an external conventional computer or an on-board fieldprogrammable gate array (FPGA) or digital signal processor (DSP), thatexecutes software, or stored instructions. In general, physicalprocessors and/or machines employed by embodiments of the presentdisclosure for any processing or evaluation may include one or morenetworked or non-networked general purpose computer systems,microprocessors, field programmable gate arrays (FPGA's), digital signalprocessors (DSP's), micro-controllers, and the like, programmedaccording to the teachings of the example embodiments of the presentdisclosure, as is appreciated by those skilled in the computer andsoftware arts. The physical processors and/or machines may be externallynetworked with the image capture device(s), or may be integrated toreside within the image capture device. Appropriate software can bereadily prepared by programmers of ordinary skill based on the teachingsof the example embodiments, as is appreciated by those skilled in thesoftware art. In addition, the devices and subsystems of the exampleembodiments can be implemented by the preparation ofapplication-specific integrated circuits or by interconnecting anappropriate network of conventional component circuits, as isappreciated by those skilled in the electrical art(s). Thus, the exampleembodiments are not limited to any specific combination of hardwarecircuitry and/or software.

Stored on any one or on a combination of computer readable media, theexample embodiments of the present disclosure may include software forcontrolling the devices and subsystems of the example embodiments, fordriving the devices and subsystems of the example embodiments, forenabling the devices and subsystems of the example embodiments tointeract with a human user, and the like. Such software can include, butis not limited to, device drivers, firmware, operating systems,development tools, applications software, and the like. Such computerreadable media further can include the computer program product of anembodiment of the present disclosure for performing all or a portion (ifprocessing is distributed) of the processing performed inimplementations. Computer code devices of the example embodiments of thepresent disclosure can include any suitable interpretable or executablecode mechanism, including but not limited to scripts, interpretableprograms, dynamic link libraries (DLLs), Java classes and applets,complete executable programs, and the like. Moreover, parts of theprocessing of the example embodiments of the present disclosure can bedistributed for better performance, reliability, cost, and the like.

Common forms of computer-readable media may include, for example, afloppy disk, a flexible disk, hard disk, magnetic tape, any othersuitable magnetic medium, a CD-ROM, CDRW, DVD, any other suitableoptical medium, punch cards, paper tape, optical mark sheets, any othersuitable physical medium with patterns of holes or other opticallyrecognizable indicia, a RAM, a PROM, an EPROM, a FLASH-EPROM, any othersuitable memory chip or cartridge, a carrier wave or any other suitablemedium from which a computer can read.

While the present disclosure has been described with reference to one ormore particular embodiments, those skilled in the art will recognizethat many changes may be made thereto without departing from the spiritand scope of the present disclosure. Each of these embodiments andobvious variations thereof is contemplated as falling within the spiritand scope of the invention. It is also contemplated that additionalembodiments according to aspects of the present disclosure may combineany number of features from any of the embodiments described herein.

What is claimed is:
 1. A system for corneal treatment, comprising: alight source configured to activate cross-linking in at least oneselected region of a cornea treated with a cross-linking agent, thelight source being configured to deliver photoactivating light to the atleast one selected region of the cornea according to a set ofparameters; and a controller configured to receive input relating to thecross-linking agent and the set of parameters for the delivery of thephotoactivating light, the controller including computer-readablestorage media storing: (A) a first set of program instructions fordetermining, from the input, cross-linking resulting from reactionsinvolving reactive oxygen species (ROS) including at least peroxides,superoxides, and hydroxyl radicals, and (B) a second set of programinstructions for determining, from the input, cross-linking fromreactions not involving oxygen, the controller being configured toexecute the first and second sets of program instructions to output acalculated amount of cross-linking in the at least one selected regionof the cornea, wherein, in response to the calculated amount ofcross-linking output by the controller, the light source is configuredto adjust at least one value in the set of parameters for the deliveryof the photoactivating light.
 2. The system of claim 1, furthercomprising an oxygen source and an oxygen delivery device configured toprovide a concentration of oxygen from the oxygen source to the at leastone selected region of the cornea, wherein the input received by thecontroller further relates to the concentration of oxygen and thecontroller is configured to execute the first and second sets of programinstructions to output the calculated amount of cross-linking basedadditionally on the concentration of oxygen.
 3. The system of claim 1,wherein the calculated amount of the cross-linking indicates athree-dimensional distribution of cross-links in the at least oneselected region of the cornea.
 4. The system of claim 3, wherein thecontroller is further configured to calculate a threshold depthcorresponding to a healing response due to the three-dimensionaldistribution of cross-links and an effect of the reactive-oxygen speciesin the at least one selected region of the cornea.
 5. The system ofclaim 3, wherein the controller is further configured to calculate abiomechanical tissue stiffness threshold depth corresponding to abiomechanical tissue response due to the three-dimensional distributionof cross-links in the at least one selected region of the cornea.
 6. Thesystem of claim 3, further comprising an oxygen source and a deliverydevice configured to provide a concentration of oxygen from the oxygensource to the at least one selected region of the cornea, wherein theconcentration of the oxygen further determines the three-dimensionaldistribution of cross-links.
 7. The system of claim 1, wherein the inputrelating to the cross-linking agent indicates a specified concentrationof the cross-linking agent and a soak time for the treatment of thecross-linking agent.
 8. The system of claim 1, wherein the first set ofprogram instructions further determines cross-linking resulting fromreactions involving reactive oxygen species (ROS) including singletoxygen.
 9. A system for corneal treatment, comprising: a light sourceconfigured to activate cross-linking in at least one selected region ofa cornea treated with a cross-linking agent, the light source beingconfigured to deliver photoactivating light to the at least one selectedregion of the cornea according to a set of parameters; an oxygen sourceand an oxygen delivery device configured to provide a concentration ofoxygen from the oxygen source to the at least one selected region of thecornea; and a controller configured to receive input relating to thecross-linking agent, the set of parameters for the delivery of thephotoactivating light, and the concentration of oxygen, the controllerincluding computer-readable storage media storing: (A) a first set ofprogram instructions for determining, from the input, cross-linkingresulting from reactions involving reactive oxygen species (ROS)including at least peroxides, superoxides, and hydroxyl radicals, and(B) a second set of program instructions for determining, from theinput, cross-linking from reactions not involving oxygen, the controllerbeing configured to execute the first and second sets of programinstructions to output a calculated amount of cross-linking in the atleast one selected region of the cornea, the calculated amount ofcross-linking indicating a three-dimensional distribution ofcross-links, wherein, in response to the calculated amount of thecross-linking activity output by the controller, at least one of: (i)the light source is configured to adjust at least one value in the setof parameters for the delivery of the photoactivating light, or (ii) theoxygen delivery device is configured to adjust a value of theconcentration of oxygen delivered to the at least one selected region ofthe cornea.
 10. The system of claim 9, wherein the controller is furtherconfigured to calculate a threshold depth corresponding to a healingresponse due to the three-dimensional distribution of cross-links and aneffect of the reactive-oxygen species in the at least one selectedregion of the cornea.
 11. The system of claim 9, wherein the controlleris further configured to calculate a biomechanical tissue stiffnessthreshold depth corresponding to a biomechanical tissue response due tothe three-dimensional distribution of cross-links in the at least oneselected region of the cornea.
 12. The system of claim 9, wherein theinput relating to the cross-linking agent indicates a specifiedconcentration of the cross-linking agent and a soak time for thetreatment of the cross-linking agent.
 13. The system of claim 12,wherein the first set of program instructions further determinescross-linking resulting from reactions involving reactive oxygen species(ROS) including singlet oxygen.
 14. A system for corneal treatment,comprising: an illumination system configured to deliver photoactivatinglight to a cross-linking agent applied to a cornea, the photoactivatinglight generating cross-linking activity with the cross-linking agent;and a controller including one or more processors and computer-readablestorage media, the controller configured to receive input relating to adesired biomechanical change in the cornea and to execute, with the oneor more processors, program instructions stored on the storage media to:determine, from a photochemical kinetic model, a three-dimensionaldistribution of cross-links for the cornea to achieve the desiredbiomechanical change in the cornea, the photochemical kinetic modelcalculating the distribution of cross-links based on cross-linking from(A) reactions involving reactive oxygen species (ROS) including at leastperoxides, superoxides, and hydroxyl radicals, and (B) reactions notinvolving oxygen, and determine at least one set of treatment parametersto achieve the distribution of cross-links, the at least one set oftreatment parameters including illumination parameters for the deliveryof the photoactivating light by the illumination system, wherein, inresponse to the determination of the at least one set of treatmentparameters, the illumination system is configured to deliver thephotoactivating light to the cornea according to the illuminationparameters.
 15. The system of claim 14, wherein the controller isconfigured to execute the program instructions to determine a pluralityof sets of treatment parameters to achieve the distribution ofcross-links, and the illumination system is configured to deliver thephotoactivating light according to the illumination parameters in aselected one of the sets of treatment parameters.
 16. The system ofclaim 15, wherein the controller configured to receive informationrelating to one or more preferences for the treatment parameters and toexecute further program instructions to determine the selected set oftreatment parameters according to the one or more preferences.
 17. Thesystem of claim 16, wherein the one or more preferences relates to adose of the photoactivating light delivered by the illumination systemaccording to the illumination parameters or a duration for the deliveryof the photoactivating light by the illumination system according to theillumination parameters.
 18. The system of claim 14, further comprisingan oxygen source and an oxygen delivery device configured to provide aconcentration of oxygen from the oxygen source to the cornea, whereinthe at least one set of treatment parameters includes oxygenationparameters for the delivery of the concentration of oxygen by the oxygendelivery device, and in response to the determination of the at leastone set of treatment parameters, the oxygen delivery device isconfigured to deliver the concentration of oxygen according to theoxygenation parameters.
 19. The system of claim 14, wherein the at leastone set of treatment parameters includes cross-linking agent parametersrelating to a concentration or a soak time for the cross-linking agentapplied to the cornea.
 20. The system of claim 14, wherein thecontroller is further configured to receive further input relating to aninitial biomechanical state of the cornea and to execute further programinstructions to determine the distribution of cross-links to achieve thedesired biomechanical change in the cornea having the initialbiomechanical state.